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Heme Synthesis Dr. Shumaila Asim Lecture # 2 1 Overview of Heme Synthesis Heme Succinyl CoA + Glycine Protoporphyrin IX ALA synthase -aminolevulinic acid Protoporphyrinogen IX Coproporphyrinogen III mitochondrial matrix cytoplasm -aminolevulinic acid Porphobilinogen Uroporphyrinogen III Uroporphyrinogen I Coproporphyrinogen III Coproporphyrinogen I Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow. 2 Heme biosynthesis • in bone marrow (85% of Hb) and liver (cytochromes) • cell location: mitochondria / cytoplasm / mitochondria • substrates: succinyl-CoA + glycine • important intermediates: ● δ-aminolevulinic acid (= 5-aminolevulinic acid, ALA) porphobilinogen (PBG = pyrrole derivate) uroporphyrinogen III (= porphyrinogen – heme precursor) protoporphyrin IX (= direct heme precursor) key regulatory enzyme: ALA synthase GLYCINE + SuccinylCoA ALA synthase -aminolevulinic acid(ALA) ALA dehydratase Porphobilinogen(PBG) hydroxymethylbilane uroporphyrinogen III coprophyrinogen III Protoporphyrinogene IX protoporphyrin IX Heme PBG deaminase Uroporphyrinogen III cosynthase Uroporphyrinogen decarboxylase Coproporphyrinogen oxidase Protoporphyrinogen oxidase Ferrochelatase δ-aminolevulinic acid (ALA) • synthesis of heme starts in mitochondria • succinyl-CoA and Gly undergo a condensation → ALA • reaction is catalyzed by enzyme ALA synthase ALA Synthase is the committed step of the heme synthesis pathway, & is usually rate-limiting for the overall pathway. Regulation occurs through control of gene transcription. Heme functions as a feedback inhibitor, repressing transcription of the ALA Synthase gene in most cells. 7 Porphobilinogen (PBG) • ALA leaves the mitochondria → cytoplasm • 2x ALA condense together to form porphobilinogen • reaction is catalyzed by porphobilinogen synthase (ALA dehydratase) COO N H pyrrole Porphobilinogen (PBG) is the first pathway intermediate that includes a pyrrole ring. COO CH2 CH2 CH2 H2C NH3 + N H Porphobilinogen (PBG) The porphyrin ring is formed by condensation of 4 molecules of porphobilinogen. Porphobilinogen Deaminase catalyzes successive PBG condensations, initiated in each case by elimination of the amino group. 9 COO- - OOC CH2 COO- CH2 CH2 CH2 NH HN NH HN CH2 CH2 COO- CH2 COO- HO CH2 CH2 CH2 CH2 COO-COO- CH2 hydroxymethylbilane COO10 COO- hydroxymethylbilane - OOC COO- uroporphyrinogen III - CH2 COO- CH2 COO CH2 CH2 CH2 CH2 CH2 CH2 NH HN NH HN CH2 COO- - OOC CH2 NH HN NH HN CH2 CH2 COO- CH2 COO- HO C C CH2 C COO- - OOC CH2 C CH2 CH2 CH2 CH2 COO-COO- CH2 COO- Uroporphyrinogen III Synthase CH2 CH2 CH2 CH2 COO- COO- Uroporphyrinogen III Synthase converts the linear tetrapyrrole hydroxymethylbilane to the macrocyclic uroporphyrinogen III. 11 - COO - protoporphyrin IX uroporphyrinogen III CH2 COO- CH2 CH2 CH2 CH OOC CH2 CH2 - CH2 COO CH3 CH CH2 H3C NH HN NH NH HN N - CH2 OOC CH2 COO- N HN H3C CH3 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 COO- COO- COO- COO- All 4 acetyl side chains are decarboxylated to methyl groups (catalyzed by Uroporphyrinogen Decarboxylase) Oxidative decarboxylation converts 2 of 4 propionyl side chains to vinyl groups (catalyzed by Coproporphyrinogen Oxidase) Oxidation adds double bonds (Protoporphyrinogen Oxidase). 12 CH2 protoporphyrin IX CH2 CH CH3 CH CH CH2 H3C NH N N Fe++ heme CH3 CH CH2 H3C Fe HN N H3C CH3 CH2 CH2 CH2 COO- N N 2H+ N H3C Ferrochelatase CH3 CH2 CH2 CH2 CH2 CH2 COO- COO- COO- Fe++ is added to protoporphyrin IX via Ferrocheletase, a homodimeric enzyme containing 2 iron-sulfur clusters. 13 Regulation of heme biosynthesis ALA synthase is a key regulatory enzyme it is an allosteric enzyme that is inhibited by an end product - heme (feedback inhibition) requires pyridoxal phosphate as a coenzyme certain drugs and steroid hormones can increase heme synthesis ● ● ● Porphobilinogen synthase is inhibited by lead ions Pb2+ in case of lead poisoning. Ferrochelatase (heme synthase) can be also inhibited by Pb2+. Its activity is influenced by availability of Fe2+ and ascorbic acid. Disorders of Heme Synthesis • Acquired: Lead poisoning • Congenital: Porphyrias • Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.) 15 16